Identification of a homozygous missense substitution in GNE. (A) Filtering strategy of whole-exome sequencing results to identify candidate variants in patients III:3 and III:5 of the same family. (B) Segregation analysis of the exome candidates in family members where DNA was available. The 3 variants (in the genes GNE, FRMPD1, and ANKRD18A) were shared by both affected children and were located within a region of homozygosity on chromosome 9p13.3. Double lines linking parents signify first-cousin unions. (C) Linear domain organization of GNE encoding the enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase. Experimental allosteric sites are based on in vitro studies (AS), region of unknown function (UF). The approximate position of amino acid substitutions (p.G416R and p.G559R) found in the family in this study and in an independent study,¹¹  respectively, are indicated and based on transcript NM_005476. del, deletion; WT, wild-type.